Volume 41 of Issue 28 | Oncogene
Authors: Datta J, Bianchi A, De Castro Silva I, Deshpande NU, Cao LL, Mehra S, Singh S, Rafie C, Sun X, Chen X, Dai X, Colaprico A, Sharma P, Dosch AR, Pillai A, Hosein PJ, Nagathihalli NS, Komanduri KV, Wilson JM, Ban Y, Merchant NB
Co-occurrent KRAS and TP53 mutations define a majority of patients with pancreatic ductal adenocarcinoma (PDAC) and define its pro-metastatic proclivity. Here, we demonstrate that KRAS-TP53 co-alteration is associated with worse survival compared with either KRAS-alone or TP53-alone altered PDAC in 245 patients with metastatic disease treated at a tertiary referral cancer center, and validate this observation in two independent molecularly annotated datasets. Compared with non-TP53 mutated KRAS-altered tumors, KRAS-TP53 co-alteration engenders disproportionately innate immune-enriched and CD8 T-cell-excluded immune signatures. Leveraging in silico, in vitro, and in vivo models of human and murine PDAC, we discover a novel intersection between KRAS-TP53 co-altered transcriptomes, TP63-defined squamous trans-differentiation, and myeloid-cell migration into the tumor microenvironment. Comparison of single-cell transcriptomes between KRAS-TP53 co-altered and KRAS-altered/TP53 tumors revealed cancer cell-autonomous transcriptional programs that orchestrate innate immune trafficking and function. Moreover, we uncover granulocyte-derived inflammasome activation and TNF signaling as putative paracrine mediators of innate immunoregulatory transcriptional programs in KRAS-TP53 co-altered PDAC. Immune subtyping of KRAS-TP53 co-altered PDAC reveals conflation of intratumor heterogeneity with progenitor-like stemness properties. Coalescing these distinct molecular characteristics into a KRAS-TP53 co-altered "immunoregulatory program" predicts chemoresistance in metastatic PDAC patients enrolled in the COMPASS trial, as well as worse overall survival.
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Science immunology
Authors: Bastard P, Vazquez S, Liu J, Laurie MT, Wang CY, Gervais A, Le Voyer T, Bizien L, Zamecnik C, Philippot Q, Rosain J, Catherinot E, Willmore A, Mitchell AM, Bair R, Garçon P, Kenney H, Fekkar A, Salagianni M, Poulakou G, Siouti E, Sahanic S, Tancevski I, Weiss G, Nagl L, Manry J, Duvlis S, Arroyo-Sánchez D, Paz Artal E, Rubio L, Perani C, Bezzi M, Sottini A, Quaresima V, Roussel L, Vinh DC, Reyes LF, Garzaro M, Hatipoglu N, Boutboul D, Tandjaoui-Lambiotte Y, Borghesi A, Aliberti A, Cassaniti I, Venet F, Monneret G, Halwani R, Sharif-Askari NS, Danielson J, Burrel S, Morbieu C, Stepanovskyy Y, Bondarenko A, Volokha A, Boyarchuk O, Gagro A, Neuville M, Neven B, Keles S, Hernu R, Bal A, Novelli A, Novelli G, Saker K, Ailioaie O, Antolí A, Jeziorski E, Rocamora-Blanch G, Teixeira C, Delaunay C, Lhuillier M, Le Turnier P, Zhang Y, Mahevas M, Pan-Hammarström Q, Abolhassani H, Bompoil T, Dorgham K, COVID HGE consortium † , French COVID study group † , COMET consortium † , Gorochov G, Laouenan C, Rodríguez-Gallego C, Ng LFP, Renia L, Pujol A, Belot A, Raffi F, Allende LM, Martinez-Picado J, Ozcelik T, Keles S, Imberti L, Notarangelo LD, Troya J, Solanich X, Zhang SY, Puel A, Wilson MR, Trouillet-Assant S, Abel L, Jouanguy E, Ye CJ, Cobat A, Thompson LM, Andreakos E, Zhang Q, Anderson MS, Casanova JL, DeRisi JL
Cancer epidemiology, biomarkers & prevention : a publication of the American Association for Cancer Research, cosponsored by the American Society of Preventive Oncology
Authors: Macauda A, Clay-Gilmour A, Hielscher T, Hildebrandt MA, Kruszewski M, Orlowski RZ, Kumar SK, Ziv E, Orciuolo E, Brown EE, Försti A, Waller RG, Machiela MJ, Chanock SJ, Camp NJ, Rymko M, Razny M, Cozen W, Varkonyi J, Piredda C, Pelosini M, Belachew AA, Subocz E, Hemminki K, Rybicka-Ramos M, Giles GG, Milne RL, Hofmann JN, Zaucha JM, Vangsted AJ, Goldschmidt H, Rajkumar SV, Tomczak W, Sainz J, Butrym A, Watek M, Iskierka-Jazdzewska E, Buda G, Robinson DP, Jurczyszyn A, Dudzinski M, Martinez-Lopez J, Sinnwell JP, Slager SL, Jamroziak K, Reis RM, Weinhold N, Bhatti P, Carvajal-Carmona LG, Zawirska D, Norman AD, Mazur G, Berndt SI, Campa D, Vachon CM, Canzian F
