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Program Official
Principal Investigator
Ludmil B Alexandrov
Awardee Organization

University Of California, San Diego
United States

Fiscal Year
2024
Activity Code
U01
Early Stage Investigator Grants (ESI)
Not Applicable
Project End Date

Mapping immuno-genomic drivers of the head and neck precancer invasive-disease transition

Globally, more than 900,000 people are diagnosed with head and neck squamous cell carcinoma (HNSCC) each year, with more that 250,000 dying annually from this cancer. Infection with human papilloma virus (HPV), a known risk factor for developing HNSCC, significantly impacts clinical prognostication. Specifically, for HPVnegative HNSCC, the most lethal subtype of head and neck cancer, less than 30% of those diagnosed survive for more than five years. The most common and lethal HPV-negative HNSCC subtype is oral cavity squamous cell carcinoma (OSCC). Importantly, most OSCCs are preceded by morphologically distinguishable precancerous lesions which are readily accessible for histological and molecular evaluation. This provides a unique opportunity for intercepting this deadly cancer in the earliest stages of its development by halting the conversion of oral precancer into invasive OSCC. Oral leukoplakia, the focus of this application, represents the most frequent type of oral premalignancy, with one in every fifty people is expected to develop OL in their lifetime. OL’s low malignant transformation rate of ~3.3% progressing to oral cancer and its highly variable natural history poses a major challenge for surveying OLs and for intercepting their malignant conversion into invasive oral cancers. To address this challenge, we hypothesize that the evolutionary transition from an OL into an OSCC is due to the immuno-genomic interactions encompassing the acquisition of somatic driver events, the gain of chromosomal instability, and the loss of effective immunosurveillance. We further hypothesize that the genomic and immune landscapes of OL in patients who subsequently develop oral cancer (progressors) will differ from those that do not develop oral cancer (non-progressors). The overall objective of this project is to elucidate the molecular and immune mechanisms by which OLs progress to OSCCs, and to develop actionable and predictive biomarkers. To achieve this objective, we will leverage well-annotated OL cohorts to generate the largest wholeexome and whole-transcriptome atlas encompassing 300 OLs, including at least 100 cancer progressors and 100 non-progressors. Further, by utilizing a spatial multiplex immuno-fluorescence platform and an unbiased RNA-sequencing approach for immuno-profiling, we will comprehensively map the immune landscapes of these 300 OLs and associate distinct immuno-genetic features with likely progression to OSCC. Lastly, our state-ofthe-art oral carcinogenesis mouse model will be used to model the transition of OL to OSCC at the single cell resolution in order to understand the role of common genomic alterations and immune surveillance in this process. Overall, this project will reveal the compendium of immuno-genetic changes that drive the evolutionary transition from an OL to an OSCC and elucidate a set of targetable immune cell population(s) and novel immune surveillance mechanisms, which can likely halt this malignant transformation.

Publications

  • Torrens L, Moody S, de Carvalho AC, Kazachkova M, Abedi-Ardekani B, Cheema S, Senkin S, Cattiaux T, Cortez Cardoso Penha R, Atkins JR, Gaborieau V, Chopard P, Carreira C, Abbasi A, Bergstrom EN, Vangara R, Wang J, Fitzgerald S, Latimer C, Diaz-Gay M, Jones D, Teague J, Ribeiro Pinto F, Kowalski LP, Polesel J, Giudici F, de Oliveira JC, Lagiou P, Lagiou A, Vilensky M, Mates D, Mates IN, Arantes LM, Reis R, Podesta JRV, von Zeidler SV, Holcatova I, Curado MP, Canova C, Fabianova E, Rodríguez-Urrego PA, Humphreys L, Alexandrov LB, Brennan P, Stratton MR, Perdomo S. The complexity of tobacco smoke-induced mutagenesis in head and neck cancer. Nature genetics. 2025 Apr;57(4):884-896. Epub 2025 Mar 31. PMID: 40164736
  • Durfee C, Bergstrom EN, Díaz-Gay M, Zhou Y, Temiz NA, Ibrahim MA, Nandi SP, Wang Y, Liu X, Steele CD, Proehl J, Vogel RI, Argyris PP, Alexandrov LB, Harris RS. Tobacco smoke carcinogens exacerbate APOBEC mutagenesis and carcinogenesis. bioRxiv : the preprint server for biology. 2025 Jan 22. PMID: 39896515
  • Díaz-Gay M, Dos Santos W, Moody S, Kazachkova M, Abbasi A, Steele CD, Vangara R, Senkin S, Wang J, Fitzgerald S, Bergstrom EN, Khandekar A, Otlu B, Abedi-Ardekani B, de Carvalho AC, Cattiaux T, Penha RCC, Gaborieau V, Chopard P, Carreira C, Cheema S, Latimer C, Teague JW, Mukeriya A, Zaridze D, Cox R, Albert M, Phouthavongsy L, Gallinger S, Malekzadeh R, Niavarani A, Miladinov M, Erić K, Milosavljevic S, Sangrajrang S, Curado MP, Aguiar S, Reis RM, Reis MT, Romagnolo LG, Guimarães DP, Holcatova I, Kalvach J, Vaccaro CA, Piñero TA, Świątkowska B, Lissowska J, Roszkowska-Purska K, Huertas-Salgado A, Shibata T, Shiba S, Sangkhathat S, Chitapanarux T, Roshandel G, Ashton-Prolla P, Damin DC, de Oliveira FH, Humphreys L, Lawley TD, Perdomo S, Stratton MR, Brennan P, Alexandrov LB. Geographic and age-related variations in mutational processes in colorectal cancer. medRxiv : the preprint server for health sciences. 2025 Feb 21. PMID: 40034755
  • Zhang T, Zhao W, Wirth C, Díaz-Gay M, Yin J, Cecati M, Marchegiani F, Hoang PH, Leduc C, Baine MK, Travis WD, Sholl LM, Joubert P, Sang J, McElderry JP, Klein A, Khandekar A, Hartman C, Rosenbaum J, Colón-Matos FJ, Miraftab M, Saha M, Lee OW, Jones KM, Caporaso NE, Wong MP, Leung KC, Agnes Hsiung C, Chen CY, Edell ES, Martínez Santamaría J, Schabath MB, Yendamuri SS, Manczuk M, Lissowska J, Świątkowska B, Mukeria A, Shangina O, Zaridze D, Holcatova I, Mates D, Milosavljevic S, Savic M, Bossé Y, Gould Rothberg BE, Christiani DC, Gaborieau V, Brennan P, Liu G, Hofman P, Homer R, Yang SR, Pesatori AC, Consonni D, Yang L, Zhu B, Shi J, Brown K, Rothman N, Chanock SJ, Alexandrov LB, Choi J, Cardelli M, Lan Q, Nowak MA, Wedge DC, Landi MT. Deciphering lung adenocarcinoma evolution and the role of LINE-1 retrotransposition. bioRxiv : the preprint server for biology. 2025 Mar 16. PMID: 40161734
  • Hanna GJ, Villa A, Nandi SP, Shi R, ONeill A, Liu M, Quinn CT, Treister NS, Sroussi HY, Vacharotayangul P, Goguen LA, Annino DJ Jr, Rettig EM, Jo VY, Wong KS, Lizotte P, Paweletz CP, Uppaluri R, Haddad RI, Cohen EEW, Alexandrov LB, William WN Jr, Lippman SM, Woo SB. Nivolumab for Patients With High-Risk Oral Leukoplakia: A Nonrandomized Controlled Trial. JAMA oncology. 2024 Jan 1;10(1):32-41. PMID: 37971722
  • Díaz-Gay M, Dos Santos W, Moody S, Kazachkova M, Abbasi A, Steele CD, Vangara R, Senkin S, Wang J, Fitzgerald S, Bergstrom EN, Khandekar A, Otlu B, Abedi-Ardekani B, de Carvalho AC, Cattiaux T, Penha RCC, Gaborieau V, Chopard P, Carreira C, Cheema S, Latimer C, Teague JW, Mukeriya A, Zaridze D, Cox R, Albert M, Phouthavongsy L, Gallinger S, Malekzadeh R, Niavarani A, Miladinov M, Erić K, Milosavljevic S, Sangrajrang S, Curado MP, Aguiar S, Reis RM, Reis MT, Romagnolo LG, Guimarães DP, Holcatova I, Kalvach J, Vaccaro CA, Piñero TA, Świątkowska B, Lissowska J, Roszkowska-Purska K, Huertas-Salgado A, Shibata T, Shiba S, Sangkhathat S, Chitapanarux T, Roshandel G, Ashton-Prolla P, Damin DC, de Oliveira FH, Humphreys L, Lawley TD, Perdomo S, Stratton MR, Brennan P, Alexandrov LB. Geographic and age variations in mutational processes in colorectal cancer. Nature. 2025 Jul;643(8070):230-240. Epub 2025 Apr 23. PMID: 40267983
  • Díaz-Gay M, Zhang T, Hoang PH, Khandekar A, Zhao W, Steele CD, Otlu B, Nandi SP, Vangara R, Bergstrom EN, Kazachkova M, Pich O, Swanton C, Hsiung CA, Chang IS, Wong MP, Leung KC, Sang J, McElderry J, Yang L, Nowak MA, Shi J, Rothman N, Wedge DC, Homer R, Yang SR, Lan Q, Zhu B, Chanock SJ, Alexandrov LB, Landi MT. The mutagenic forces shaping the genomic landscape of lung cancer in never smokers. medRxiv : the preprint server for health sciences. 2024 May 17. PMID: 38798417
  • Otlu B, Alexandrov LB. Evaluating topography of mutational signatures with SigProfilerTopography. Genome biology. 2025 May 20;26(1):134. PMID: 40394581
  • Durfee C, Bergstrom EN, Díaz-Gay M, Zhou Y, Temiz NA, Ibrahim MA, Nandi SP, Wang Y, Liu X, Steele CD, Proehl J, Vogel RI, Argyris PP, Alexandrov LB, Harris RS. Tobacco smoke carcinogens exacerbate APOBEC mutagenesis and carcinogenesis. Research square. 2025 Jun 3. PMID: 40502742
  • Otlu B, Alexandrov LB. Evaluating topography of mutational signatures with SigProfilerTopography. bioRxiv : the preprint server for biology. 2024 Jan 9. PMID: 38260507
  • Khandekar A, Hoang PH, Luebeck J, Díaz-Gay M, Zhao W, McElderry JP, Hartman C, Miraftab M, Lee OW, Barnao KM, Bergstrom EN, Yang Y, Nowak MA, Rothman N, Homer R, Yang SR, Lan Q, Wedge DC, Yang L, Chanock SJ, Zhang T, Alexandrov LB, Landi MT. Examining the Role of Extrachromosomal DNA in 1,216 Lung Cancers. bioRxiv : the preprint server for biology. 2025 Jul 24. PMID: 40501879
  • Wu X, Adame-Garcia SR, Koshizuka K, Vo PTT, Hoang TS, Sato K, Izumi H, Goto Y, Allevato MM, Wood KC, Lippman SM, Gutkind JS. Oncogenic HRAS Induces Metformin Resistance in Head and Neck Cancer by Promoting Glycolytic Metabolism. Cancer prevention research (Philadelphia, Pa.). 2024 Dec 3;17(12):571-583. PMID: 39463147
  • Zhao X, Liu B, William WN, Tsanov KM, Ho YJ, Barriga FM, Lim RJ, Trifas M, Khandekar A, Du Y, Lowe SW, Dubinett SM, Davoli T, Lippman SM. Interferon Epsilon Loss Is Elusive 9p21 Link to Immune-Cold Tumors, Resistant to Immune Checkpoint Therapy, and Endogenous CXCL9/10 Induction. Journal of thoracic oncology : official publication of the International Association for the Study of Lung Cancer. 2024 Dec 24. Epub 2024 Dec 24. PMID: 39725169
  • Bergstrom EN, Abbasi A, Díaz-Gay M, Galland L, Ladoire S, Lippman SM, Alexandrov LB. Deep Learning Artificial Intelligence Predicts Homologous Recombination Deficiency and Platinum Response From Histologic Slides. Journal of clinical oncology : official journal of the American Society of Clinical Oncology. 2024 Oct 20;42(30):3550-3560. Epub 2024 Jul 31. PMID: 39083703
  • Abbasi A, Steele CD, Bergstrom EN, Khandekar A, Farswan A, McKay RR, Pillay N, Alexandrov LB. HRProfiler Detects Homologous Recombination Deficiency in Breast and Ovarian Cancers Using Whole-Genome and Whole-Exome Sequencing Data. Cancer research. 2025 Jul 2;85(13):2504-2513. PMID: 40327608
  • Díaz-Gay M, Vangara R, Barnes M, Wang X, Islam SMA, Vermes I, Duke S, Narasimman NB, Yang T, Jiang Z, Moody S, Senkin S, Brennan P, Stratton MR, Alexandrov LB. Assigning mutational signatures to individual samples and individual somatic mutations with SigProfilerAssignment. Bioinformatics (Oxford, England). 2023 Dec 1;39. (12). PMID: 38096571
  • Wang CP, Yu KJ, Chen TC, Tsai MS, Kang CJ, Chien CY, Engels EA, Hua CH, Hsu WL, Chang YL, Dawsey SM, Wentzensen N, Shi J, Mao F, Cheung LC, Katki HA, Boyd E, Wu CT, Gutkind JS, Molinolo A, Limbach AL, Lingen MW, Lou PJ, Chen CJ, Hildesheim A, Chaturvedi AK. Multistate oral carcinogenesis-A prospective cohort study and a parallel case-control study in Taiwan. Oral oncology. 2025 Mar;162:107210. Epub 2025 Feb 12. PMID: 39947008
  • Sears TJ, Pagadala MS, Castro A, Lee KH, Kong J, Tanaka K, Lippman SM, Zanetti M, Carter H. Integrated Germline and Somatic Features Reveal Divergent Immune Pathways Driving Response to Immune Checkpoint Blockade. Cancer immunology research. 2024 Dec 3;12(12):1780-1795. PMID: 39255339
  • Senkin S, Moody S, Díaz-Gay M, Abedi-Ardekani B, Cattiaux T, Ferreiro-Iglesias A, Wang J, Fitzgerald S, Kazachkova M, Vangara R, Le AP, Bergstrom EN, Khandekar A, Otlu B, Cheema S, Latimer C, Thomas E, Atkins JR, Smith-Byrne K, Cortez Cardoso Penha R, Carreira C, Chopard P, Gaborieau V, Keski-Rahkonen P, Jones D, Teague JW, Ferlicot S, Asgari M, Sangkhathat S, Attawettayanon W, Świątkowska B, Jarmalaite S, Sabaliauskaite R, Shibata T, Fukagawa A, Mates D, Jinga V, Rascu S, Mijuskovic M, Savic S, Milosavljevic S, Bartlett JMS, Albert M, Phouthavongsy L, Ashton-Prolla P, Botton MR, Silva Neto B, Bezerra SM, Curado MP, Zequi SC, Reis RM, Faria EF, de Menezes NS, Ferrari RS, Banks RE, Vasudev NS, Zaridze D, Mukeriya A, Shangina O, Matveev V, Foretova L, Navratilova M, Holcatova I, Hornakova A, Janout V, Purdue MP, Rothman N, Chanock SJ, Ueland PM, Johansson M, McKay J, Scelo G, Chanudet E, Humphreys L, de Carvalho AC, Perdomo S, Alexandrov LB, Stratton MR, Brennan P. Geographic variation of mutagenic exposures in kidney cancer genomes. Nature. 2024 May;629(8013):910-918. Epub 2024 May 1. PMID: 38693263
  • Boysen G, Alexandrov LB, Rahbari R, Nookaew I, Ussery D, Chao MR, Hu CW, Cooke MS. Investigating the origins of the mutational signatures in cancer. Nucleic acids research. 2025 Jan 7;53. (1). PMID: 39778866
  • Faraji F, Ramirez SI, Clubb LM, Sato K, Burghi V, Hoang TS, Officer A, Anguiano Quiroz PY, Galloway WMG, Mikulski Z, Medetgul-Ernar K, Marangoni P, Jones KB, Cao Y, Molinolo AA, Kim K, Sakaguchi K, Califano JA 3rd, Smith Q, Goren A, Klein OD, Tamayo P, Gutkind JS. YAP-driven malignant reprogramming of oral epithelial stem cells at single cell resolution. Nature communications. 2025 Jan 8;16(1):498. PMID: 39779672