In their latest paper, published in the journal Oncogene, they used live imaging and electron microscopy to study the cellular activities associated with successful metastasis, including the expression of a group of proteins called cadherins, which help cells bind together. Since these proteins enable cancer cells to anchor to new sites in the body, it may be possible to disrupt metastasis by blocking cadherin-mediated binding.

The research was led by Mark Alber, a distinguished professor of applied mathematics at UC Riverside, and M. Sharon Stack, a Kleiderer-Pezold professor of biochemistry and director of Notre Dame Harper Cancer Research Institute.

As primary ovarian tumors metastasize, they shed both single cells and clusters of cells, called multicellular aggregates (MCAs), into the pelvis and abdomen. To study exactly how metastasis occurs, the researchers quantified the interactions between epithelial ovarian cancer (EOC) cells and three-dimensional models of the abdomen wall. They showed when EOC cells acquired N-cadherin (Ncad), an event that occurs in human EOC tumors, they could penetrate and attach to the abdomen wall. Furthermore, MCAs dispersed prior to invasion as a large cohort of cells, showing that cell to cell junctional integrity (i.e. attachment at the single cell level) was needed for successful metastasis.

Alber said unlike results observed in other cancers, ovarian cancer cells do not appear to exhibit a ‘leader-follower’ type of collective cell invasion.

“Interestingly, co-culture of Ncad-expressing cells with cells expressing E-cadherin (Ecad) did not promote invasion of the Ecad-expressing cells, demonstrating that Ncad-expressing cells do not simply lead the way for other cell populations to follow,” Stack said.

The findings emphasize the importance of Ncad in ovarian cancer metastasis and provide the rationale to support pre-clinical studies using Ncad-blocking molecules as a therapeutic strategy to suppress EOC metastatic anchoring.

The group is using these results to develop computational models of cancer cell invasion. Future studies will also use patient samples, which will be provided by collaborators from the City of Hope, in Duarte, Calif. for combined modeling and experimental approaches to obtain novel insights into the cellular mechanisms of ovarian cancer metastasis.

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Materials provided by University of California – Riverside. Original written by Sarah Nightingale. Note: Content may be edited for style and length.

In most neurodegenerative diseases, misfolded proteins aggregate to form an insoluble clump called amyloid. Many amyloid-forming proteins, including tau in Alzheimer’s disease and alpha-synuclein in Parkinson’s disease, contain the amino acid proline, whose unique structure induces a bend in the amino acid chain. Those bends contribute to stacking of adjacent regions of the protein, thus promoting amyloid formation. During normal protein folding, CyP40 latches on to prolines, orienting them into their characteristic chain-bending conformation, but like most enzymes, it can also operate in reverse, helping to unbend the chain.

The researchers found that CyP40 could reduce the amount of aggregated tau, converting it into a more soluble form. In a mouse model of an Alzheimer’s-like disease, experimental expression of CyP40 preserved brain neurons and rescued cognitive deficits. The same enzyme also disaggregated alpha-synuclein, an aggregate associated with Parkinson’s disease. This is the first time that CyP40 has been shown to disaggregate an amyloid responsible for a neurodegenerative disease.

Exactly how CyP40 reduces aggregation is not yet clear, and the authors provide two possibilities. The enzyme may bind to aggregated protein and, by reversing the proline bend, help unstack and separate the amino acid chain. Support for this model comes from the observation that the enzyme was less effective at reducing aggregates when its action was inhibited. Alternatively, the enzyme may bind to the protein before it forms aggregates, sequestering it and thus preventing it from clumping.

Understanding more about the exact mechanism of the enzyme may help point toward a therapeutic strategy centered on proline’s role in amyloid formation. “The finding that Cyp40 can untangle clumps of tau and alpha-synuclein suggests that it, or one of the more than 40 other human proteins with similar activity, may have a role to play in treating neurodegenerative disease,” Blair said.

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In the case of butterflies, the cabbage white Pieris rapae in particular, scientists have found male butterfly ejaculate — a complex package designed to deliver sperm — also contains a dose of valuable life-extending nutrients that female butterflies devour like candy.

But receiving this parcel of goodness comes at a cost — male dominance.

It comes covered in a hard shell that takes three days to digest, during which time the female cannot mate again, says University of Cincinnati biologist Nathan Morehouse.

Recent interdisciplinary research led by Morehouse in the Morehouse Research Lab and Nathan Clark, biologist in the Clark Research Lab at the University of Pittsburgh looked closer at the complex structures and mechanisms within male butterfly ejaculates and the adaptive responses in the female butterfly reproductive tract.

The researchers hope these study findings will aid in understanding the complex human reproductive cycle and the occasional problems that originate on a molecular level. The authors published their co-evolutionary results in the June journal Proceedings of the National Academy of Sciences.

“As scientists, we already knew that male butterfly ejaculates were three-fold complex structures we call spermatophores — composed of an outer envelope, an inner matrix of fluids and a bolus of sperm,” says UC’s Morehouse. “What we didn’t know and found through our research is that these three structures are distinctly different in protein composition, are separately stored in the male reproductive tract and are transferred sequentially to the female reproductive tract during mating.”

Why such an elaborate process for such a tiny butterfly? Control over female reproduction, Morehouse says.

Because the spermatophore occupies much of the female reproductive tract, she cannot mate again until it is gone. Males make it tough for her by encasing the spermatophore in a hard shell. This delay benefits the male by assuring more of his sperm fertilize her eggs.

Method behind his madness

“In this set of species, and in many insects, they have what’s called last male sperm precedence,” says Clark. “When another male comes in and mates, his sperm either displaces the first male’s sperm or pushes them to the back.”

Occasionally, individual male seminal fluids and female enzymes won’t work together efficiently, creating an imbalance that can result in low egg fertilization. The researchers say looking at how female butterflies have resolved this obstacle may open the curtain for correcting similar protein-enzyme imbalances in human infertility.

Using high-tech computerized technology such as mass spectrometry and older standard biochemical processes, the researchers determined that the tiny winged macho-men transfer 13 percent of their total body weight through their spermatophore complex during the mating process. But surprisingly, only 2 percent of that is actually sperm.

The rest of the complex goody bag of proteins, carbohydrates, lipids and other compounds play all sorts of other important roles in reproduction — not the least of which is a way for the males to prevent the female from mating again for about three to four days, says Morehouse.

On the flip side, he says females benefit much more by mating often for a number of reasons:

Females like a variety in the genetics of the offspring they produce, as some male genotypes are better than others and this assures her the most successful outcome.

Females crave the delicious protein nutrients males pass along during mating that provide life-extending cell repair — sort of like going to a butterfly spa — so the more the better.

These protein nutrients also help females build eggs. We estimate that a female who mates 2-3 times may build 30-40 percent of the eggs she lays from proteins the male transfers during copulation. So male mates are actually funding her reproduction.

“To keep a female from remating, the males have developed a hard outer shell around the precious nutrients that are especially desirable by females to repair their cells and live longer,” says Clark. “This hard outer shell gets transferred behind the bolus of sperm and acts as a copulatory plug that prevents the female from being able to mate again with other males — hopefully insuring his sperm as the cocktail that fertilizes the female’s eggs when she lays them.”

Wait! Not so fast

“I was fascinated to discover that females are actually very well equipped to quickly digest the nuptial gift from the male,” says Camille Meslin-Auclair, post-doctoral biologist who performed most of the analysis working at the University of Pittsburgh. “Even more fascinating are the mechanical and biochemical tools she possesses to dissolve this outer shell.”

In an evolutionary twist of fate, these clever little females have developed an extraordinary way to break free from the male’s control.

“We discovered a surprising mechanical chewing device inside the female reproductive tract lined with a spectacular array of tooth-like structures that can gnaw through the hard outer shell in a matter of hours,” says Morehouse. “Without this mechanism we affectionately call the ‘vagina dentata,’ it would likely take a week or more to dissolve the hard protective shell with just her enzymes alone.”

By looking at reproduction as both a source of cooperation and conflict between the sexes, the researchers are finding clues from this study on a behavioral and molecular level that can be an important link for solving certain unexplained causes of human infertility.

“Reproduction is a very interesting social interface where males and females have a conversation,” says Morehouse. “That conversation often begins with courtship, but doesn’t stop after mating happens.

“It becomes a negotiation between the molecules of both sexes for the shared goal of producing offspring.”

As the researchers understand incompatibilities between butterflies on a molecular level, they plan to track how these creatures evolve and develop certain enzymes and proteins to solve this tug of war.

Morehouse and Clark hope new findings eventually unlock some of the mysteries of human infertility that exist on a similar stage between male seminal fluids and female reproductive enzymes.

“These cabbage white butterflies are one of the most common butterflies in the world and very common in Cincinnati,” says Morehouse.

“There is magic all around us and the lovely thing about science is that sometimes clues that might actually help with health issues like human infertility can come from a butterfly in your own backyard.”