The Most Lethal Part of Cancer

Graduate Division

The most lethal part of cancer is that it spreads.

Stopping the spread of cancer, known as metastasis, would be a leap forward in treatment. However, first, we must better understand why and how metastasis happens.

Most cancers start as a primary tumor named for the tissue in which it originates. The cancer then spreads to other organs, with many cancers commonly spreading to the lymph nodes, lungs, spleen, liver and thymus.

There remain a few big questions about why metastases happen. First, what are the underlying genetic changes that lead to metastasis? And secondly, how do metastases develop and spread from the primary tumor? The development could be linear, where an single metastasis occurs and then spreads from one organ to the next. Or the development could be parallel, with multiple metastases originating from the primary tumor and spreading separately.

A recent paper from the Balmain lab at UCSF has begun to answer these questions.

This work published in Nature Medicine on November 2nd used mouse models to track the spread of carcinoma, a type of cancer that originates in the skin and the linings of the body’s cavities. The lead author, graduate student Melissa McCreery, took specific steps to most accurately mimic human cancer in these models.

“We used mice crossed to a strain of wild mice so that every mouse in our cohort was genetically unique. Using this, we could model some of the genetic diversity seen in the human population in our mouse population,” said McCreery.

In addition, McCreery followed a treatment course similar to humans, surgically removing the primary carcinoma. As in humans, this removal allowed for extended survival of the mice and led to the development of metastases, which could then be analyzed.

McCreery extracted DNA from tumors in each stage and in all affected organs, and sequenced them to examine what mutations led to metastasis and track their course of development. As a comparison, normal tissue and early-stage forms of the carcinoma were also sequenced.

By comparing mutations found in the sequences of the metastases to the sequence of the primary tumor, they were able to determine how related each of the tumors were to each other.

Strikingly, McCreery found that the sequences of the metastases were equally related to the primary tumor, suggesting that they all disseminated at the same time in parallel, rather than sequentially.

Furthermore, in comparing sequences, McCreery found that not all primary carcinomas led to metastases. In fact, in a single mouse, different primary carcinomas coexisted, some that had led to a metastasis and others that had not.

Having directly comparable samples allowed the authors to delve into the question of why some primary tumors cause metastasis, and others do not. In particular, the authors were able to identify mutations in a couple key genes that may contribute to a tumor’s ability to spread. Furthermore, “in our unpublished data, we found that the tumors that metastasize, tend to have more mutations than the tumors that did not metastasize,” McCreery said.

The results from this work have a direct relevance to cancer treatment in the clinic.

“First, it’s important that we think about what types of interventions and surgeries are actually going to help people. If we believe that tumors spread in parallel to many different organ sites at once, then taking out lymph nodes and doing a localized surgery is not necessarily going to be helpful for patient survival,” said McCreery.

“Second, we observed that tumors seemed to spread very early. They had probably already spread by the time we saw the primary tumor. If tumors are spreading before they’re ever seen by a doctor or a patient, the question becomes how do you keep a distant, small metastasis in check, rather than how do you keep the primary tumor from spreading in the first place.”

While future work is necessary to determine if this parallel model of metastasis is true for all cancer types, this work is an important step forward in understanding how metastasis happens and how to better treat it.