Maria T. Diaz-Meco,

Weill Cornell Scientists Discover New Set of Biomarkers To Predict Colon Cancer Survival Interview with:
Jorge Moscat, PhD
Maria T. Diaz-Meco, PhD

Jorge Moscat

Maria T. Diaz-Meco,

Principal Investigators
Moscat & Diaz-Meco Laboratories
Department of Pathology and Laboratory Medicine
Weill Cornell Medicine
New York, NY What is the background for this study?
Would you describe the two different histological premalignant states?

Response: Although much effort is devoted to understanding the biology and pathology of established malignant tumors and the formation of metastasis in order to identify new and more efficacious treatment approaches, much less is understood of how tumors initiate from normal cells.

This is extremely important because treating incipient benign neoplasia should be easier and less toxic than treated already aggressive and disseminated cancer cells. In the case of colorectal cancer (CRC), routinary colonoscopies might identify still benign lesions that can be either “serrated” or “conventional” but that all present with reduced levels of two proteins called the aPKCs. As the tumor evolves, if the aPKCs are not upregulated, then the cancer becomes very aggressive and with very limited therapeutic options. Our work identifies precisely the initial mechanisms that determine if a benign adenoma would progress towards an aggressive phenotype. A full comprehension of these initial steps will lead to effective preventive therapies to stop cancer before it starts. What are the main findings? What could cause the initial reduction in levels of aPKC?

Response:  A key aspect of the most malignant type of CRC is the appearance of intestinal cells that acquire features of fetal-gastric primitive cells, which are very invasive and that predicts poor survival of the patients that express them. Our data reported in this paper in Developmental Cell and in a previous study that we published in Cancer Cell unravel the precise mechanisms whereby they are generated and open the possibility of potential therapies. How aPKC are reduced during the initial phases of tumor initiation is still unknow and constitute one of the most urgent lines of research in our labs. However, although we still do not know how the aPKCs are reduced, thanks to our studies we know now that they are critical for CRC initiation and malignancy, and we have a very good idea of how they work and how we can target them therapeutically.

Interestingly, we also found that the deficiency in the aPKCs unexpectedly trigger the loss of intestinal stem cells leading to a vicious cycle of intestinal damage and defective regeneration underlying tumor initiation even before oncogenic mutations occur. We propose that this newly identified mechanism is common to the start of all forms of colorectal tumors. Interrogation of pre-malignant human colon specimens demonstrates that the signaling pathways discovered in our mouse and organoid systems, are of pathophysiological relevance, highlighting its great potential significance in the clinic. What should readers take away from your report?

Response: That we have discovered a new set of biomarkers to predict the survival of CRC and that have identified a new therapeutic strategy ready to be tested in the clinic. What recommendations do you have for future research as a results of this study?

Response: More effort should be devoted to investigate the very initial steps of cancer initiation because those would be easier to target and stop tumorigenesis very early before cancer cells accumulate mutations and chromosomal aberration that will lead to more malignant features much more difficult to treat. Is there anything else you would like to add?

Response: Just that based on the findings reported in these two recent papers, we are ready to go to a clinical trial to test our discoveries.

Citation: Hiroto Kinoshita, Anxo Martinez-Ordoñez, Tania Cid-Diaz, Qixiu Han, Angeles Duran, Yu Muta, Xiao Zhang, Juan F. Linares, Yuki Nakanishi, Hiroaki Kasashima, Masakazu Yashiro, Kiyoshi Maeda, Ana Albaladejo-Gonzalez, Daniel Torres-Moreno, José García-Solano, Pablo Conesa-Zamora, Giorgio Inghirami, Maria T. Diaz-Meco, Jorge Moscat,

Epithelial aPKC deficiency leads to stem cell loss preceding metaplasia in colorectal cancer initiation, Developmental Cell,2024,ISSN 1534-5807,

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Last Updated on June 6, 2024 by Marie Benz MD FAAD