SP9: Dissecting adaptation of the tumor microenvironment upon targeting of mutp53 subtypes in colorectal and pancreatic cancer
Missense mutations of the tumor suppressor p53 are critical molecular alterations in clinically relevant gastrointestinal tumors including adenocarcinomas of colon or pancreas. P53 mutations provide tumor cells with gain-of-function (GOF) features promoting malignant growth, metastasis, and therapy resistance by deregulation of the tumor microenvironment. It is now important to understand how p53 missense mutations affect the tumor microenvironment including immune cell infiltration and suppression to find means to overcome therapy resistance.
The group of Ramona Schulz-Heddergott demonstrated missense mutant p53R248Q GOF features by activation of STAT3. A GOF prerequisite is the HSP90-mediated stabilization of such p53 mutants. The group also found that p53R248Q profoundly affects intratumoral infiltration with neutrophils suggesting novel targets for immunotherapeutic interventions. The Kühnel group has established a transposon-based, genetically versatile mouse model of in-situ pancreatic cancer for expression of various missense p53 mutants allowing their side-by-side comparison on a molecular and immunological level in vivo.
We have now teamed up to characterize mutant p53-induced molecular and immunophenotypical alterations using various murine tumor models and high-resolution methodology including RNAseq, multiplex-IHC and spectral flow cytometry. The PhD- and MD-candidates of the first cohort (Schulz-Heddergott group) will focus on mutant p53-dependent alterations in an inducible mouse model of colorectal cancers that allows temporal control of mutant p53 on/off states. The PhD- and MD-candidates of the second cohort (Kühnel lab) will compare most prominent cancer -associated missense mutations of p53 in vivo regarding their impact on the composition and function of tumor infiltrating immune cells. Together, the two project partners want to decipher the mechanisms how missense p53 mutations shape tumor growth characteristics and the tumor immune microenvironment in order to identify new targets for tailored immune interventions.
