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FRIMEDBIO-Fri prosj.st. med.,helse,biol

Decoding the Cancer Stem Cell Niche in Triple-Negative Breast Cancer

Alternativ tittel: Finne nisjen til kreftstamceller i trippel-negativ brystkreft

Tildelt: kr 7,8 mill.

Trippel-negativ brystkreft er den mest aggressive formen for brystkreft. Én tredel av pasientene får tilbakefall eller har ingen effekt av behandlingen. Dette til tross for tilgang til flere nye behandlinger. En mulig forklaring for hvorfor pasienter ikke blir friskere, er at såkalte "kreftstamceller" er til stede i svulsten. Kreftstamceller er kreftcellene som har dannet svulsten. De har blitt vist til å bidra til behandlingsmotstand, samt utvikling og spredning av kreften. Kreftstamceller utgjør derfor de farligste kreftcellene i en svulst. Å bli kvitt kreftstamceller kan potensielt kurere kreften. Celler, også kreftceller, overlever sjelden alene, og er avhengige av et miljø, eller «nisje», med andre celler rundt, for å klare seg. Dette gjelder også kreftstamceller. Dessverre, så mangler vi metoder for å identifisere kreftstamceller og deres nisje, så vi vet lite om dem. I dette prosjektet vil vi derfor utvikle nye metoder ved hjelp av komplekse dataalgoritmer for å finne kreftstamcellnisjen i trippel-negativ brystkreft. Det endelige målet i dette prosjektet er å finne nye behandlinger mot brystkreft, og forhåpentligvis andre krefttyper, for bedre overlevelse og livskvalitet hos pasienter.

Triple-negative breast cancer (TNBC) is the most aggressive type of breast cancer. Although promising new drugs based on PARP inhibition and immunotherapy can extend survival in selected patients, 30-40% of patients relapse or fail therapy. Increasing evidence suggest that TNBC tumors harbor cancer stem cells, which have been implicated in cancer development, maintenance, metastasis, and therapy resistance. However, how the microenvironment in TNBC tumors shapes the development of cancer stem cells and their niche is unknown. Importantly, understanding the interplay between the tumor microenvironment (TME) and the cancer stem cells could reveal novel therapeutic targets and improve patient outcome. Current methods to study cancer stem cells and their surrounding niche rely on the use of protein labels called antibodies, but are limited to a small number of known markers, and may miss rare cell states. Commercial assays for single cell and spatial transcriptomics have provided novel opportunities to study over 20,000 markers simultaneously, but either lack spatial information or single cell resolution. We hypothesize that in silico decoding of the TNBC cancer stem cell niche will uncover novel candidates for targeted therapies that could transform TNBC treatment. To address this hypothesis, we propose to (i) develop CytoNICHE, an integrative computational framework to resolve the developmental hierarchy of the cancer stem cell niche; (ii) apply it to TNBC tumors profiled by scRNA-seq and spatial transcriptomics to generate an atlas of the TNBC cancer stem cell niche in relation to therapy; and (iii) prioritize factors from the TME that regulate the development and maintenance of cancer stem cells and test them in a human TNBC organoid system. If successful, this proposal will reveal novel candidates for drug targeting that could vastly improve TNBC outcomes, and the resulting framework will facilitate the investigation of the cancer stem cell niche in other cancers.

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FRIMEDBIO-Fri prosj.st. med.,helse,biol

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