Researchers at UConn Health, Yale, and Johns Hopkins have identified that some cancer cells can “cheat” through escaping constraints imposed by lack of oxygen, allowing the cancer cells to proceed to grow.

This discovery was recently published in Cell Systems by Kshitiz, assistant professor within the Department of Biomedical Engineering, in collaboration with researchers Chi V. Dang at Johns Hopkins and Andre Levchenko at Yale.

Nearly a decade ago, the researchers observed an odd phenomenon while cancer cells under hypoxia-;or a scarcity of oxygen.

As tumors grow and turn into large, they run out of oxygen and latest blood vessels are created. This ends in scarcity of oxygen, called hypoxia. Under hypoxia, cells are imagined to decelerate their growth, but after all, cancers proceed to grow larger. This presents a conundrum, yet unsolved.”

Kshitiz, Assistant Professor, Department of Biomedical Engineering

The researchers determined that a small variety of cells were “cheating”-;or rewiring their signaling to permit them to divide and grow. Solving the mystery of how the cells were cheating-;and the way this phenomenon applied to cancer diagnoses-; soon became a spotlight of the researchers’ work.

Under hypoxia, cells stabilize a protein called HIF-1, which is a master regulator of oxygen response within the cells. When oxygen goes down, HIF-1 signaling becomes high and takes the cells to a non-functioning state. HIF-1 directs the cell division machinery to stop working, jump starts anaerobic respiration using a great quantity of glucose, and makes cells secrete proteins to bring blood vessels towards themselves.

Within the study, the researchers noted that a small percentage of cells didn’t stabilize HIF-1, but as an alternative oscillated the protein-;moving it up and down. As HIF-1 oscillated, and went from as much as all the way down to up again, cells could escape the HIF-1-;imposed pause. In this manner, these oscillating cells cheated and proceed to divide, despite very low oxygen levels.

“To search out cheaters inside a population of cancer cells, that are themselves cheating the traditional cells, is interesting at so many levels,” Kshitiz says.

“Now we have observed oscillations in lots of systems, but oscillations in HIF-1 activity was not recorded before, and it is really remarkable,” Levchenko adds. “We’re particularly excited about how oscillations like these may be recognized as a signal triggering specific genes.”

Moreover, researchers found that the cancer cells communicate with one another, allowing cells to sense other cells’ density. When HIF-1 is high due to hypoxia, cells produce energy without oxygen. A byproduct is lactate, the identical molecule that offers us cramps during exercise if the muscles should not well oxygenated. Cancers accumulate lots of lactate of their environment. Kshitiz worked with researcher Junaid Afzal at University of California San Francisco to work out the detailed mechanism that caused lactate to destabilize HIF-1.

“Excess lactate forces cells to undergo respiration, even when oxygen is scarce, and that caused degradation of HIF-1 in lysosomes, the recycling centers in a cell,” says Afzal.

Nevertheless, questions remain-;are these observations under a microscope meaningful in real cases of cancer? Current technologies don’t offer an efficient strategy to test these predictions in animal subjects-;let alone human subjects.

Kshitiz, together with Yasir Suhail, a postdoctoral student in Kshitiz’s lab at UConn Health, used this newfound information and checked out the genetic makeup of various cancers that occur in humans.

“What we found was truly astounding,” says Kshitiz. “Most genes behaved as expected, but there was a gaggle of genes which behaved opposite to what is anticipated in hypoxia. It didn’t make much sense; why should genes which activate in hypoxia, turn off when hypoxia is oscillating? Clearly something is at play.”

To know further, Suhail checked out these genes in all human cancers and located a universal phenomenon. The genes that were turned off by oscillations were turned off in most cancers-;showing that the oscillation in HIF-1 levels could possibly decrease tumor suppressor genes and contribute to cancer growth in most cancers.

Kshitiz says, “Probably the most interesting aspect is the universality of the phenomenon in all cancers. It seems this effect is pan-cancer, and never just in any cancer.”

The research-;unraveling this unique phenomenon-; answers several conundrums about cancer, while opening latest lines of scientific inquiry.

“It’s a large collaboration across many institutions, a testament to how deep scientific questions require the mixing of many forms of expertise to return together,” says Kshitiz.

Source:

University of Connecticut

Journal reference:

Kshitiz, et al. (2022) Lactate-dependent chaperone-mediated autophagy induces oscillatory HIF-1α activity promoting proliferation of hypoxic cells. Cell Systems. doi.org/10.1016/j.cels.2022.11.003.