Cell reprogramming involves changing the expression of top-level regulatory genes, picking targets that will radically change cell form and function. Given a suitable recipe, many of which have been established, forms of cell reprogramming can be used to change somatic cells into stem cells, or change somatic cells of one type into somatic cells of another type. In the other direction, numerous approaches can be used to guide stem cells into differentiating into varieties of somatic cell.
A cancerous cell adopts some of the characteristics of a stem cell, primarily the unrestricted replication that is the hallmark of cancer, and sometimes some of the characteristics of other somatic cell types. Cancer stem cells are thought to exist for many forms of cancer, a class of cancerous cell in which stem cell characteristics are much more prevalent. Cancer stem cells support a cancer and its growth in much the same way that normal stem cells support a tissue.
Given all of this, it seems reasonable to suppose that it is possible to reprogram or otherwise guide a cancer cell into becoming a normal somatic cell. This could be an interesting basis for a cancer therapy, with all the usual caveats about whether or not the reprogramming therapy is inherently targeted to the cancer, or whether it would need to be delivered carefully to avoid side-effects in non-cancerous tissue. Today's open access paper offers an example of a form of reprogramming that turns one specific type of cancer cells into what appear to be normal somatic cells. It will be interesting to see whether this approach gains any traction or wider adoption, or whether killing cancerous cells will always tend to be the more efficient way forward.
Dysregulation of tissue-specific gene expression programs is a hallmark of cancer. Such dysregulation leads to cancer-promoting gene expression programs and, in various types of cancer, the consequent reprogramming of cells into those with stem or progenitor (stem/progenitor) properties. A study of cancer initiation revealed that normal differentiated cells with oncogenic mutations remain in a nonmalignant state until they undergo cellular reprogramming into a stem/progenitor state. This suggests that differentiated cells have an inherent resistance mechanism against malignant transformation and indicates that cellular reprogramming is indispensable for malignancy. Thus, we speculated that malignant properties might be eradicated if the tissue-specific gene expression program is reinstated.
In colorectal cancer, cellular differentiation is impeded through processes involving both oncogenic mutations and microenvironmental alterations. This cancer provides a model for exploring whether the malignant cells could be converted to normal-like cells through restoration of the tissue-specific gene expression program. To address this challenge in a systematic way, we employed a computational framework to identify the core factors to revert cancer cells back to their normal state. A recent computational framework for inferring gene regulatory networks (GRN) has effectively applied to the cell fate conversion study through identification of master regulators of tissue-specific gene expression programs.
Here, we reconstructed normal colon-specific GRNs and colorectal cancer-specific GRNs, and identified core transcription factors (TF) for differentiation of colorectal cancer cells. We further identified SET Domain Bifurcated 1 (SETDB1) as a key factor that hinders the function of core TFs. We demonstrated that SETDB1 depletion effectively reestablishes the normal colon-specific gene expression profile and induces a postmitotic differentiated state in three stem-like colorectal cancer cell lines and patient-derived colon cancer organoids by recapitulating the transcriptional activities of the core TFs.